An Alternative Binding Mode of IGHV3-53 Antibodies to the SARS-CoV-2 Receptor Binding Domain

Nicholas C Wu; Meng Yuan; Hejun Liu; Chang-Chun D Lee; Xueyong Zhu; Sandhya Bangaru; Jonathan L Torres; Tom G Caniels; Philip J M Brouwer; Marit J van Gils; Rogier W Sanders; Andrew B Ward; Ian A Wilson

doi:10.1016/j.celrep.2020.108274

An Alternative Binding Mode of IGHV3-53 Antibodies to the SARS-CoV-2 Receptor Binding Domain

Cell Rep. 2020 Oct 20;33(3):108274. doi: 10.1016/j.celrep.2020.108274. Epub 2020 Sep 29.

Authors

Affiliations

¹ Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA; Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA.
² Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
³ Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam Infection and Immunity Institute, 1105AZ Amsterdam, the Netherlands.
⁴ Department of Medical Microbiology, Amsterdam UMC, University of Amsterdam, Amsterdam Infection and Immunity Institute, 1105AZ Amsterdam, the Netherlands; Department of Microbiology and Immunology, Weill Medical College of Cornell University, New York, NY 10021, USA.
⁵ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA.
⁶ Department of Integrative Structural and Computational Biology, The Scripps Research Institute, La Jolla, CA 92037, USA; IAVI Neutralizing Antibody Center, The Scripps Research Institute, La Jolla, CA 92037, USA; Consortium for HIV/AIDS Vaccine Development (CHAVD), The Scripps Research Institute, La Jolla, CA 92037, USA; The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA, 92037, USA. Electronic address: wilson@scripps.edu.

Abstract

IGHV3-53-encoded neutralizing antibodies are commonly elicited during SARS-CoV-2 infection and target the receptor-binding domain (RBD) of the spike (S) protein. Such IGHV3-53 antibodies generally have a short CDR H3 because of structural constraints in binding the RBD (mode A). However, a small subset of IGHV3-53 antibodies to the RBD contain a longer CDR H3. Crystal structures of two IGHV3-53 neutralizing antibodies here demonstrate that a longer CDR H3 can be accommodated in a different binding mode (mode B). These two classes of IGHV3-53 antibodies both target the ACE2 receptor binding site, but with very different angles of approach and molecular interactions. Overall, these findings emphasize the versatility of IGHV3-53 in this common antibody response to SARS-CoV-2, where conserved IGHV3-53 germline-encoded features can be combined with very different CDR H3 lengths and light chains for SARS-CoV-2 RBD recognition and virus neutralization.

Keywords: COVID-19; SARS-CoV-2; antibodies; receptor-binding domain; spike protein; x-ray crystallography.

MeSH terms

Antibodies, Neutralizing / immunology*
Antibodies, Viral / immunology*
Betacoronavirus / immunology*
COVID-19
Complementarity Determining Regions / immunology
Coronavirus Infections / virology
Crystallography, X-Ray
Humans
Immunoglobulin Heavy Chains / immunology
Neutralization Tests
Pandemics
Pneumonia, Viral / virology
Protein Domains / immunology
SARS-CoV-2
Spike Glycoprotein, Coronavirus / immunology*

Substances

Antibodies, Neutralizing
Antibodies, Viral
Complementarity Determining Regions
Immunoglobulin Heavy Chains
Spike Glycoprotein, Coronavirus
spike protein, SARS-CoV-2

Abstract

MeSH terms

Substances

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